Many neurodegenerative diseases, including spinal and bulbar muscular atrophy (SBMA) and ALS, result from protein misfolding and accumulation due to a variety of both genetic and environmental causes. SBMA is an adult-onset neuromuscular disease that is caused by polyglutamine expansion within the androgen receptor (AR);it is related mechanistically to other neurodegenerative diseases caused by polyglutamine expansion. Although the precise pathway leading to neuronal dysfunction and death is unknown, the evaluation of transgenic mouse and cell models of these diseases have yielded many mechanistic clues. Moreover, our transgenic cell and mouse models of SBMA reproduce the upstream events of polyglutamine-dependent proteolysis and aggregation, making these models highly useful for the analysis of novel therapeutic avenues that affect these upstream events. SBMA stands apart from other polyglutamine diseases in that its onset and progression are androgen-dependent. Our long-term objectives are to use transgenic and cell models that we have developed to evaluate hormone-based therapies, and to identify steps in the metabolism of the expanded AR that are impacted by such compounds. We predict that these studies will reveal new targets, involved in early stages of disease, for therapeutic intervention. To reach these goals, we propose two specific aims: 1) To evaluate the efficacy of AR antagonists in modulating disease in SBMA. 2) To determine steps in the pathogenic metabolism of the expanded AR impacted by these compounds, in order to identify new therapeutic targets involved in the altered AR metabolism in SBMA. We anticipate that results from these studies will lead us to new therapies, not only for SBMA, but potentially for other protein misfolding diseases as well. Public Health Relevance: Polyglutamine diseases represent a larger family of neurodegenerative diseases characterized by protein misfolding and accumulation;these diseases include Alzheimer's disease, Huntington's disease, Parkinson's disease and amyotrophic lateral sclerosis (ALS). Therapeutic strategies designed to promote the normal folding and turnover of aberrantly accumulated proteins target upstream events in the pathogenic pathway and are thus, in many ways, independent of the downstream pathogenic mechanisms. The studies proposed here will test novel therapeutic strategies and identify new targets, with the goal of developing therapeutic interventions for both SBMA and other protein accumulation diseases.